OVERALL SUMMARY Prostate cancer (PCA) is one of the most common cancers in the Western hemisphere, with extreme clinical and molecular heterogeneity. In 2015, over 221,800 men were diagnosed with?and 27,540 died from?PCA in the United States. Our Weill Cornell Medicine (WCM) SPORE in PCA will take a novel precision medicine approach to patient care, which will align our translational research goals with the care of men across the PCA spectrum. The earliest possible detection of aggressive PCA will avoid less effective late-stage therapies. We will study how to improve risk assessment in men with localized PCA to enable optimal treatment choices, including active surveillance (AS). Men with advanced PCA, despite treatment with next generation androgen deprivation therapy (ADT), succumb to drug resistance and disease progression. We need to optimize care through novel biomarker and treatment strategies to change lethal PCA to a chronic manageable disease. We are mindful that knowledge from other fields can augment our research. We will actively use the Developmental Research Program to bring investigators from across a rich, multi-institutional landscape to focus on PCA translational research. A sustainable SPORE program requires development of the careers of junior faculty (Career Enhancement Program), who will be the leaders in the field for years to come. Horizontal and vertical scientific collaborations will ensure that we leverage expertise and experience across other SPOREs, the Early Detection Research Network (EDRN), and the Stand Up 2 Cancer (SU2C) and Prostate Cancer Foundation (PCF) programs. Lastly, we will ensure that resources and data generated from our studies will be made available to the research community. Our overarching goal is to impact PCA care from initial diagnosis through management of advanced state disease using precision medicine approaches to improve current clinical care. In summary, the WCM SPORE in PCA will be a major hub for paradigm-shifting translational research. We will establish new approaches to treating PCA, which will result in improved patient survival and quality of life.